A year of COVID-19 GWAS results from the GRASP portal reveals potential genetic risk factors

Abstract

Host genetic variants influence the susceptibility and severity of several infectious diseases, and the discovery of genetic associations with coronavirus disease 2019 (COVID-19) phenotypes could help to develop new therapeutic strategies to decrease its burden. Between May 2020 and June 2021, we used COVID-19 data released periodically by UK Biobank and performed 65 genome-wide association studies in up to 18 releases of COVID-19 susceptibility (n = 18,481 cases in June 2021), hospitalization (n = 3,260), severe outcomes (n = 1,244), and deaths (n = 1,104), stratified by sex and ancestry. In coherence with previous studies, we observed two independent signals at the chr3p21.31 locus (rs73062389-A, odds ratio [OR], 1.21 (P = 4.26 × 10^-15) and rs71325088-C, OR, 1.62 [P = 2.25 × 10^-9]) modulating susceptibility and severity, respectively, and a signal influencing susceptibility at the ABO locus (rs9411378-A; OR, 1.10; P = 3.30 × 10^-12), suggesting an increased risk of infection in non-O blood groups carriers. Additional signals at the APOE (associated with severity and death) LRMDA (susceptibility in non-European) and chr2q32.3 (susceptibility in women) loci were also identified, but did not replicate in independent datasets. We then devised an approach to extract variants suggestively associated (P < 10^-5), exhibiting an increase in significance over time. When applied to the susceptibility, hospitalization and severity analyses, this approach revealed the known RPL24, DPP9, and MAPT loci, respectively, among hundreds of other signals. These results, freely available on the GRASP portal, provide insights on the genetic mechanisms involved in COVID-19 phenotypes.

Keywords: COVID-19; GWAS; MUC4; genetics; trajectory.

Figure 1

Analysis workflow The design of our study includes two phases. First, GWAS were performed for all 65 analyses, and genome-wide significant associations were identified. Second, we focused on suggestive associations that increased in significance over time.

Figure 2

Evolution of significant signals associated with COVID-19 susceptibility, hospitalization, severity and death in UKB participants of EUR, using Population as controls (A–D) Results of susceptibility, hospitalization, severity, and death analyses. For each sub-figure, the top panel represents the evolution in significance (as -log10 p-values on y-axis) of signals reaching genome wide significance at least once across all data releases analyzed. The middle panel represent the mean age of cases in each data release. The bottom panel represent the number of cases in each data release. For sub-figure A, a representation of these signals across the COVID-19hgi releases is available as Figure S51.